Heart failure is the leading cause of mortality globally with higher incidence in developed nations. Cardiac dilation is a common clinical phenomenon observed in several cardiac diseases, such as post-myocardial infarction and heart failure. While in the early stages, only portions of the heart may be affected. In advanced stages, the complete heart may be enlarged causing serious problems including arrhythmias or leakage of the cardiac valves. Cardiac dilation is a frequent reason for subjecting a patient to heart transplantation. Today various approaches have been proposed to reverse cardiac dilation including drug therapy, device therapy and cell-based therapy.
The drug-based therapy includes administration of beta-adrenergic receptor blockers. Drug therapy is a quite old approach to reverse pathologic effects of cardiac dilation. However, healing of myocardial dilation or heart failure cannot be achieved by drug therapy alone.
A further approach is device therapy. For example, to assist the failing heart cope with its pumping function, left ventricular assist devices can be implanted. Alternative device strategies include implantation of means restricting further dilation including bags. For example, WO 2008/058917 describes pouch-like constructs for preventing heart distension. Moreover, complete artificial hearts are under development, although not yet prepared for use.
Moreover, cell-based therapies are described in the art including the application of bone marrow derived mesenchymal stem cells as well as human pluripotent stem cells, including embryonic stem cells, induced pluripotent stem cells, pathogenic stem cells, and cardiac progenitor cells. However, sources and application thereof are limited. Moreover, experimental data show that paracrine support may have a therapeutic effect in cardiac dilation therapy. For example, it has been suggested to introduce IGF-1, however, a clear therapeutic benefit of systemically applied IGF-1 has not been demonstrated yet.
Quite recently heart muscle tissue engineering has come into the focus of scientists. Tissue engineering has been developed to biophysically support the failing heart, but also to provide in vitro tests for drug development and studies of organogenesis. With respect to heart muscle repair the main goals are to (i) add contractile elements to the failing heart for functional support and (ii) provide restraint similar to the approaches where bags are to be placed over the dilated heart, thus, restricting further dilation, but fully humanized. For example the use of scaffolds either in synthetic or biological environments and seeding cardiomyocytes have been used. WO 2008/058917 describes pouch-like constructs for preventing heart distension wherein engineered tissue is used for obtaining a pouch-like structure. Mammalian engineered heart tissues have been developed for drug screening and therapeutic applications, e.g. Zimmermann et al. Biotechnol. Bioeng. (2000), 68(1), 106 to 14. It was possible that the mammalian engineered heart tissues had coordinated beating with directed force development and heart muscle like physiology and pharmacological responses. The pouch-like structure described in WO 2008/058917 is based on said mammalian engineered heart tissue. This mammalian engineered heart tissue includes cardiomyocytes. The engineered heart tissue may also be obtained from heart tissue other than cardiomyocytes. For example, fibroblasts, smooth muscle cells etc. may be used.
However, despite the recent increased focus on developing advanced models of engineered tissues, several clinical challenges remain to be addressed: Engineered cardiac structures should be of a clinically relevant size and thickness and consist of immunologically tolerable cell populations in a matrix similar to the host heart. In addition, these structures must also be able to connect to the host blood supply, propagate electrical pulses which must be synchronised with the host myocardium and subsequently generate sufficient contractile force to aid in blood circulation.